4-Aryliquinazolines and the use thereof as nhe-3 inhibitors

ABSTRACT

The invention relates to compounds of the formula (I) in which Ar is X-substituted phenyl or naphthyl, which is additionally substituted by R 3  and R 4 , Y or X is H, NR 6 R 7  or a saturated 5-7-membered ring having two N atoms, R 1 , R 2 , R 3  and R 4  are each, independently of one another, H, A, OA, Hal, CF 3 , OH, NO 2 , NH 2 , NHA, NA 2 , NH—CO-A, NH—CO-Ph, SA, SO-A, SO 2 -A, SO 2 -Ph, CN, OCF 3 , CO-A, CO 2 H, CO 2 A, CO—NH 2 , CO—NHA, CO—NA 2 , SO 2 NH 2 , SO 2 NHA, SO 2 NA 2 , or phenyl which is unsubstituted or monosubstituted or polysubstituted by A, OA, Hal or CF3, and salts and solvates thereof, and to the use thereof as NHE-3 inhibitors.

The invention relates to compounds of the formula I

in which

-   Ar is X-substituted phenyl or naphthyl, which is additionally    substituted by R³ and R⁴,-   Y is-   X is H, NR⁶R⁷ or a saturated 5-7-membered ring having two N atoms,-   R¹, R², R³-   and R⁴ are each, independently of one another, H, A, OA, Hal, CF₃,    OH, NO₂, NH₂, NHA, NA₂, NH—CO-A, NH—CO-Ph, SA, SO-A, SO₂-A, SO₂-Ph,    CN, OCF₃, CO-A, CO₂H, CO₂A, CO—NH₂, CO—NHA, CO—NA₂, SO₂NH₂, SO₂NHA,    SO₂NA₂, or phenyl which is unsubstituted or monosubstituted or    polysubstituted by A, OA, Hal or CF₃,-   A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,-   Hal is F, Cl, Br or I,-   R⁵ is H, A, OH, NO₂, phenyl which is unsubstituted or    monosubstituted or polysubstituted by A, OA, Hal or CF₃, an    amino-protecting group or-   R⁶ and R⁷ are each, independently of one another, H, A, phenyl which    is unsubstituted or monosubstituted or polysubstituted by A, OA, Hal    or CF₃, benzyl, an amino-protecting group or —(CH₂)_(n)NR¹⁰R¹¹,-   R⁸ and R⁹ are each, independently of one another, H or A,-   R¹⁰-   and R¹¹ are each, independently of one another, H, A, phenyl which    is unsubstituted or monosubstituted or polysubstituted by A, OA, Hal    or CF₃, benzyl or an amino-protecting group,-   Z is 0 or 1, and-   n is 2, 3 or 4,    and salts, solvates and stereoisomers thereof, including mixtures    thereof in all ratios, and pharmaceutically usable derivatives    thereof, in particular physiologically tolerated salts and solvates    thereof,    with the proviso that compounds in which X is H and simultaneously z    is 0 are excluded.

The invention likewise relates to the use of the compounds of theformula I and their salts and solvates as NHE-3 inhibitors.

Other inhibitors of the sodium/proton exchanger subtype 3 have alreadybeen described, for example in EP 0 825 178.

The compounds excepted by the proviso have already been described in DE10043667.

Quinazolinylguanidine derivatives have been described by V. I. Shvedovet al. in Pharm. Chem. J. (Engi. transl.) 1980, 14, 532-538 or in Khim.Farm. Zh. 1980, 14, 38-43, and by S. C. Bell et al. in J. Med. Pharm.Chem. 1962, 5, 63-69.

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

Surprisingly, it has been found that the compounds of the formula I andtheir salts are well tolerated and inhibit sodium/proton exchangersubtype 3 and at the same time have improved bioavailability due totheir increased water solubility.

The compounds of the formula I can be employed as medicament activeingredients in human and veterinary medicine.

It is known that the Na⁺/H⁺ exchanger represents a family having atleast six different isoforms (NHE-1 to NHE-6), all of which have alreadybeen cloned. While subtype NHE-1 is distributed ubiquitously in alltissues throughout the body, the other NHE subtypes are expressedselectively in specific organs, such as in the kidney or in the lumenwall and contra-luminal wall of the small intestine. This distributionreflects the specific functions that the various isoforms serve, namelyon the one hand regulation of the intracellular pH and cell volume bysubtype NHE-1 and on the other hand Na⁺ absorption and resorption in theintestine and kidney by isoforms NHE-2 and NHE-3. Isoform NHE-4 has beenfound principally in the stomach. Expression of NHE-5 is restricted tothe brain and neuronal tissue. NHE-6 is the isoform that forms thesodium/proton exchanger in the mitochondria.

The isoform NHE-3 is expressed in particular in the apical membrane ofthe proximal renal tubuli; an NHE-3 inhibitor therefore exerts, interalia, a protective action on the kidneys.

The therapeutic use of a selective inhibitor for NHE-3 isoforms ismanifold. NHE-3 inhibitors inhibit or reduce tissue damage and cellnecrosis after pathophysiological hypoxic and ischaemic events whichresult in an activation of the NHE activity, as is the case during renalischaemia or during the removal, transport and reperfusion of a kidneyduring a kidney transplant.

The compounds of the formula I have a cytoprotective action in that theyprevent the excessive absorption of sodium and water into the cells oforgans undersupplied with oxygen.

The compounds of the formula I have a hypotensive action and aresuitable as medicament active ingredients for the treatment ofhypertonia. They are furthermore suitable as diuretics.

The compounds of the formula I, alone or in combination with NHEinhibitors of other subtype specificity, have an antiischaemic actionand can be used in the case of thromboses, atherosclerosis, vascularspasms, for the protection of organs, for example kidney and liver,before and during operations, and in the case of chronic or acute renalfailure.

They can furthermore be used for the treatment of strokes, cerebraloedema, ischaemia of the nervous system, various forms of shock, forexample allergic, cardiological, hypovolemic or bacterial shock, and forimproving breathing drive in, for example, the following states: centralsleep apnoea, cot death, postoperative hypoxia and other breathingdisorders.

Through combination with a carboanhydrase inhibitor, breathing activitycan be further improved.

The compounds of the formula I have an inhibiting effect on theproliferation of cells, for example fibroblast cell proliferation andthe proliferation of the smooth muscle cells, and can therefore be usedfor the treatment of illnesses in which cell proliferation is a primaryor secondary cause. The compounds of the formula I can be used againstdelayed complications of diabetes, cancer illnesses, fibrotic illnesses,endothelial dysfunction, organ hypertrophia and hyperplasia, inparticular in prostate hyperplasia or prostate hypertrophia.

They are furthermore suitable as diagnostic agents for the determinationand differentiation of certain forms of hypertonia, atherosclerosis,diabetes and proliferative illnesses.

Since the compounds of the formula I also have an advantageous effect onthe level of serum lipoproteins, they can be employed, alone or incombination with other medicaments, for the treatment of an increasedblood fat level.

The invention relates to the use of compounds of the formula I accordingto Claim 1 and their physiologically acceptable salts and/or solvatesfor the preparation of a medicament for the treatment of thrombosis,ischaemic states of the heart, of the peripheral and central nervoussystem and of strokes, ischaemic states of peripheral organs andextremities and for the treatment of shock states.

The invention furthermore relates to the use of compounds of the formulaI according to Claim 1 and their physiologically acceptable salts and/orsolvates for the preparation of a medicament for use in surgicaloperations and organ transplants and for the preservation and storage oftransplants for surgical measures.

The invention also relates to the use of compounds of the formula Iaccording to Claim 1 and their physiologically acceptable salts and/orsolvates for the preparation of a medicament for the treatment ofillnesses in which cell proliferation is a primary or secondary cause,for the treatment or prophylaxis of disorders of fat metabolism ordisturbed breathing drive.

The invention furthermore relates to the use of compounds of the formulaI according to Claim 1 and their physiologically acceptable salts and/orsolvates for the preparation of a medicament for the treatment of renalischaemia, ischaemic intestinal illnesses or for the prophylaxis ofacute or chronic renal illnesses.

Methods for the identification of substances which inhibit sodium/protonexchanger subtype 3 are described, for example, in U.S. Pat. No.5,871,919.

The compounds of the formula I are, in addition, suitable for thetreatment of bacterial and parasitic illnesses.

For all radicals in the compounds of the formula I which occur more thanonce, such as, for example, A, their meanings are independent of oneanother.

The term hydrates and solvates of the compounds of the formula I istaken to mean, for example, the hemi-, mono- or dihydrates, and the termsolvates is taken to mean, for example, alcohol addition compounds, suchas, for example, with methanol or ethanol.

In the formulae above, A is alkyl, is linear or branched and has 1, 2,3, 4, 5 or 6 carbon atoms. A is preferably methyl, furthermore ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermorealso pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-,2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, or 1,1,2- or1,2,2-trimethylpropyl.

OA is preferably methoxy, ethoxy, propoxy, isopropoxy or butoxy.

Hal is preferably F, Cl or Br, but also I, in particular F, Cl or Br.

Above and below, Ph is an unsubstituted phenyl radical, unless statedotherwise.

Ar is preferably phenyl which is monosubstituted by X and, for example,A, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, propoxy, butoxyor CF₃. Ar is particularly preferably one of the following radicals:

in which R³, R⁴ and X are as defined above.

X is preferably NR⁶R⁷, a 5- to 7-membered ring having 2 N atoms or thefollowing radical:

in which R¹² is H, A, Ph, benzyl or an amino-protecting group, such as,for example, BOC or CBO and in particular H, A or phenyl.

In particular, X is H, NA₂ or a radical from the following group:

R⁵ is preferably H, A, OH, NO₂ or an amino-protecting group, inparticular H, A, OH or NO₂.

R⁶ and R⁷ are preferably simultaneously H, independently of one anotherH, A, benzyl or —(CH₂)_(n)NA₂.

R⁸ and R⁹ are preferably H or methyl, in particular H.

R¹⁰ and R¹¹ are preferably H, A, benzyl or phenyl, in particular H,methyl or benzyl.

z is preferably 0. n is preferably 2.

The term “amino-protecting group” is known in general terms and relatesto groups which are suitable for protecting (blocking) an amino groupagainst chemical reactions, but can easily be removed after the desiredchemical reaction has been carried out elsewhere in the molecule.Typical of such groups are, in particular, unsubstituted or substitutedacyl, aryl, aralkoxymethyl and aralkyl groups. Since theamino-protecting groups are removed after the desired reaction (orreaction sequence), their nature and size are furthermore not crucial;however, preference is given to those having 1-20, in particular 1-8,carbon atoms. The term “acyl group” covers acyl groups derived fromaliphatic, araliphatic, aromatic or heterocyclic carboxylic acids orsulfonic acids and in particular alkoxycarbonyl, aryloxycarbonyl andespecially aralkoxycarbonyl groups. Examples of amino-protecting groupsof this type are alkanoyl, such as acetyl, propionyl and butyryl;aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl or toluyl;aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl,ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl)and 2-iodoethoxycarbonyl; alkenyloxycarbonyl, such as allyloxycarbonyl(Aloc), aralkyloxycarbonyl, such as CBZ (“carbobenzoxy”, synonymous withZ), 4-methoxybenzyloxycarbonyl (MOZ), 4-nitrobenzyloxycarbonyl or9-fluorenylmethoxycarbonyl (FMOC); 2-(phenylsulfonyl)ethoxycarbonyl;trimethylsilylethoxycarbonyl (Teoc), or arylsulfonyl, such as4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr). The amino-protectinggroup is preferably formyl, acetyl, propionyl, butyryl, phenylacetyl,benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBZ(“carbobenzoxy”), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or benzyl.

The invention relates in particular to the compounds of the formula I inwhich at least one of the said radicals has one of the preferredmeanings indicated above, and to the use thereof.

Preference is furthermore given to compounds of the formula I and saltsand solvates thereof in which at least one of the radicals R¹, R², R³and R⁴ has one of the following meanings:

Hal, A, OH, NO₂, NH₂, NHA, NA₂, NH—CO-A, NH—CO-Ph, SA, SO-A, SO₂-A,SO₂-Ph, CN, OCF₃, CO-A, CO₂H, CO₂A, CO—NH₂, CO—NHA, CO—NA₂, SO₂NH₂,SO₂NHA, SO₂NA₂, or phenyl which is unsubstituted or monosubstituted orpolysubstituted by A, OA, Hal or CF₃.

Of the compounds of the formula 1, particular preference is given tothose whose radical R¹ is Cl, in particular in position 6, and thosewhose radical R³ is methyl, in particular in position 4′.

Compounds of the formula I whose radical R³ is methyl, in particular inposition 4′, have particularly pronounced selectivity of binding to theNHE-3 receptor.

Preference is furthermore given to the compounds of the formulae IA, IBand IC:

in which R¹, R², Ar and Y are as defined above.

In particular, R¹ in the formulae IA, IB and IC is H, while R² is Hal orin particular Cl.

Y preferably adopts one of the following meanings:

Y particularly preferably has one of the following meanings:

Particular preference is furthermore given to the following compounds I1to I10 and salts and solvates thereof:

The hydrochlorides and p-toluenesulfonates of the compounds of theformulae I1 to I10 are very particularly preferred.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants which are known per se, but arenot mentioned here in greater detail.

The starting materials can, if desired, also be formed in situ, so thatthey are not isolated from the reaction mixture, but instead areimmediately converted further into the compounds of the formula I.

The compounds of the formula I are preferably prepared by reactingcompounds of the formula II

in which R¹, R² and Ar are as defined above,with 1-cyanoguanidine or a correspondingly N-alkylated or N-arylated1-cycanoguanidine of the formula NC—Y, in which Y is as defined aboveand z is 0.

The reaction can be carried out in a solvent, preferably an inertsolvent.

Examples of suitable solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide,N-methylpyrrolidone (NMP) or dimethylformamide (DMF); nitriles, such asacetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbondisulfide; carboxylic acids, such as formic acid or acetic acid; nitrocompounds, such as nitromethane or nitrobenzene; esters, such as ethylacetate, or mixtures of the said solvents.

DMF, water or an alcohol is preferably used.

The reaction is very particularly preferably carried out without asolvent, i.e. in the melt, at temperatures between 100 and 200° C.

The presence of an acidic catalyst, such as AlCl₃, TiCl₄,p-toluenesulfonic acid, BF₃, acetic acid, sulfuric acid, oxalic acid,POCl₃ or phosphorus pentoxide, is advantageous.

A preferred variant comprises employing at least one of the reactantsalready as a salt, for example as the hydrochloride.

A further valuable method for the preparation of the compounds of theformula I comprises reacting, instead of a compound of the formula NC—Y,a compound of the formula IIIHN═CX—Y  IIIin which

-   X is —S-alkyl, —S-aryl, —O-alkyl or —O-aryl,-   Y is as defined above, where z is 0, alkyl is preferably as defgined    above for A, and aryl is as defined above for Ar,    with a compound of the formula II.

Finally, the compounds of the formula I can be prepared by reaction ofcompounds of the formula IV

in which Ar, Hal, R¹ and R² are as defined above and Hal is inparticular Cl, with a compound of the formula HY, in which Y is asdefined above. HY is particularly preferably guanidine or a compound ofthe following formula:

in which R⁵ is as defined above.

This reaction is preferably carried out in the presence of a strongbase, such as alkali metal alkoxide or strongly basic amines. The basesused are particularly preferably sodium methoxide, sodium ethoxide,potassium methoxide, potassium ethoxide, potassium tert-butoxide, DBN,DBU or DABCO.

The solvents used for the reaction of compounds of the formula IV withcompounds of the formula HY are preferably DMSO, NMP or DMF.

The compounds of the formula IV can be obtained by preparation methodswhich are known per se.

The compounds of the formula IV are particularly preferably prepared byreaction of the compounds of the formula V

Vin which R¹, R² and Hal are as defined above,a)with boronic acids of the formula Ar—B(OH)₂ in the presence of apalladium compound, such as, for example,bis(triphenylphosphine)palladium(II) chloride in the form of a Suzukicoupling. Many variants of this reaction have already been disclosed inthe literature (for example S. L. Buchwald and J. M. Fox, The StremChemiker, 200, 18, 1), Okabe et al., Tetrahedron, 1995, 51, 1861 to1866; Curd et al. J. Chem. Soc. 1948, 1759 to 1766). orb)with tributyltin compounds of the formula Ar—Sn(n-C₂H₅)₃ in the form ofa Stile coupling (for example J. K. Stille Angew. Chem. Int. Ed. Engl.1986, 25, 508).

The present application likewise relates to the process for thepreparation of the compounds of the formula V.

In some cases, it may be appropriate only to form the radicals R¹, R²,R³ and R⁴ and other functional groups after the reaction of thecompounds of the formula II with the compounds of the formula NC—Y orthe compounds of the formula III, for example by removal of a protectinggroup, ether cleavage or hydrogenation of nitro groups to amino groups.

Correspondingly, it may likewise be appropriate only to form theradicals R¹, R², R³ and R⁴ and other functional groups after thereaction of the compounds of the formula IV with the compounds of theformula HY by the above-mentioned measures.

The compounds of the formula I in which X is NR⁶R⁷ or a saturated5-7-membered ring having two N atoms are preferably synthesised from thehalogen compounds of the formula VI

by palladium-catalysed amidation using the corresponding nitrogen bases,preferably HNR⁶R⁷ or the following nitrogen base:

in which R⁶, R⁷ and R¹² are as defined above.

Reactions of this type have been described, for example, by Buchwald andHartwig (R. Stürmer, Ang. Chem. 1999, 111, 3509 to 3510; L. Buchwald etal. J. Am. Chem. Soc. 1998, 120, 9722 to 9723). Besides a suitablepalladium catalyst, such as, for example, Pd(OAc)₂ or Pd₂(dba)₃, thechoice of ligand, in particular, is of crucial importance for thesuccess of the reaction. Examples of suitable ligands are2-(di-tert-butylphosphinyl)-biphenyl,2-dimethylamino-2′-(di-tert-butylphosphinyl)biphenyl, FcPtPtBu2 or2,2′-bis(dicyclohexylphosphino)-1,1′-binaphthyl.

Before the reaction, any free amino groups present should be protected,for example by means of amino-protecting groups.

The present application likewise relates to the novel compounds of theformulae II, IV and VI.

A base of the formula I can be converted into the associatedacid-addition salt using an acid, for example by reaction of equivalentamounts of the base and the acid in an inert solvent, such as ethanol,followed by evaporation. Suitable acids for this reaction are, inparticular, those which give physiologically acceptable acids. Thus, itis possible to use inorganic acids, for example sulfuric acid, nitricacid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid,phosphoric acids, such as orthophosphoric acid, or sulfamic acid,furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinicacid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaricacid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinicacid, isonicotinic acid, methane- or ethanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids,and laurylsulfuric acid. Salts with physiologically unacceptable acids,for example picrates, can be used for the isolation and/or purificationof the compounds of the formula I.

The invention furthermore relates to the use of the compounds of theformula I as NHE-3 inhibitors and/or their physiologically acceptablesalts for the preparation of pharmaceutical preparations, in particularby non-chemical methods. In this case, they can be converted into asuitable dosage form together with at least one solid, liquid and/orsemiliquid excipient or assistant, and, if desired, in combination withone or more further active ingredients.

The invention furthermore relates to pharmaceutical preparationscomprising at least one NHE-3 inhibitor of the formula I and/or one ofits physiologically acceptable salts and solvates.

These preparations can be used as medicaments in human or veterinarymedicine. Suitable excipients are organic or inorganic substances whichare suitable for enteral (for example oral), parenteral or topicaladministration and do no react with the novel compounds, for examplewater, vegetable oils, benzyl alcohols, alkylene glycols, polyethyleneglycols, glycerol triacetate, gelatine, carbohydrates, such as lactoseor starch, magnesium stearates, talc or Vaseline. Suitable for oraladministration are, in particular, tablets, pills, coated tablets,capsules, powders, granules, syrups, juices or drops, suitable forrectal administration are suppositories, suitable for parenteraladministration are solutions, preferably oil-based or aqueous solutions,furthermore suspensions, emulsions or implants, and suitable for topicalapplication are ointments, creams or powders, or transdermally inpatches.

The novel compounds may also be lyophilised and the resultantlyophilisates used, for example, for the preparation of injectionpreparations. The preparations indicated may be sterilised and/orcomprise assistants, such as lubricants, preservatives, stabilisersand/or wetting agents, emulsifiers, salts for modifying the osmoticpressure, buffer substances, colorants and flavours and/or a pluralityof further active ingredients, for example one or more vitamins.

Suitable pharmaceutical preparations for administration in the form ofaerosols or sprays are, for example, solutions, suspensions or emulsionsof the active ingredient of the formula I in a pharmaceuticallyacceptable solvent.

The compounds of the formula I and their physiologically acceptablesalts and solvates can be used for the treatment and/or prophylaxis ofthe illnesses or illness states described above.

In general, the substances according to the invention are preferablyadministered in doses between about 0.1 and 500 mg, in particularbetween 1 and 10 mg, per dosage unit. The daily dose is preferablybetween about 0.001 and 10 mg/kg of body weight. However, the specificdose for each patient depends on a wide variety of factors, for exampleon the efficacy of the specific compound employed, on the age, bodyweight, general state of health, sex, on the diet, on the time andmethod of administration, on the excretion rate, medicament combinationand severity of the particular illness to which the therapy applies.Oral administration is preferred.

EXAMPLES

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means that water is added if necessary,the mixture is adjusted, if necessary, to a pH between 2 and 10,depending on the constitution of the end product, the mixture isextracted with ethyl acetate or dichloromethane, the phases areseparated, the organic phase is dried over sodium sulfate andevaporated, and the product is purified by chromatography on silica geland/or by crystallisation. m.p. stands for melting point.

Example 1

A mixture of 1.00 g of compound 1, 0.60 g of di-tert-butyl dicarbonate(2), 20.0 ml of dimethylformamide and 1.20 g of potassium carbonate isheated at 60° C. overnight. Water is added to the reaction mixture, themixture is filtered, and the residue is subjected to conventionalwork-up, giving compound 3.

Example 2

A mixture of 100 mg of compound 3, 600 mg of di-tert-butyl dicarbonate(2) and 5 ml of dichloromethane is stirred at 50° C. for 4 hours. Thesolvent is removed, and the residue is subjected to conventionalwork-up, giving compound 4.

Example 3

0.242 g of compound 4, 0.16 g of tert-butyl 1-piperazylcarboxylate and0.170 g of sodium tert-butoxide are added under a nitrogen atmosphere toa solution of 60 mg of palladium(II) acetate and 100 mg oftri-tert-butylphosphine in 5 ml of xylene. The mixture is stirred atroom temperature for 24 hours, water is added, and the mixture issubjected to conventional work-up, giving compound 6.

Example 4

20 mg of trifluoroacetic acid are added to 1.50 g of compound 6 with icecooling, and the mixture is stirred at room temperature for one hour.All the volatile components are removed, the residue is dissolved in 50ml of water, and 1 N sodium hydroxide solution is added dropwise untilthe mixture is alkaline. The resultant precipitate is filtered off withsuction, dissolved in 20 ml of methanol and precipitated by addition ofmethanolic hydrochloric acid solution. Filtration and conventionalwork-up give compound 7 (m.p. 245° C.).

Example 5

A mixture of 0.10 g of compound 8 and 0.152 g of compound 9 in 1.0 ml of1-methyl-2-pyrrolidone is stirred at room temperature for 2 hours. Thereaction mixture is subsequently filtered, the residue is dissolved in amixture of methanol and dichloromethane, and methanolic hydrochloricacid solution is added. Cooling, re-filtration and conventional work-upgive compound 10.

Example 6

A mixture of 0.75 g of compound 8, 0.40 g of nitroguanidine (11) and0.40 ml of DABCO in 5 ml of 1-methyl-2-pyrrolidone is stirred at 80° C.for 6 hours. Conventional work-up of the reaction mixture gives compound12.

Example 7

A mixture of 5.00 g of compound 13, 2.91 g of tolylboronic acid (14),0.30 g of bis(triphenylphosphine)palladium(II) chloride and 1.2 g ofpowdered sodium hydroxide in 60 ml of diglyme is stirred at 130° C. forsix hours. Water is subsequently added to the reaction mixture, which issubjected to conventional work-up, giving compound 15.

Example 8

A mixture of 1.45 g of compound 8 and 0.58 g of DABCO in 15 ml ofdimethyl sulfoxide is stirred at room temperature for 2 hours, and 2.66g of hydroxyguanidine sulfate 1-hydrate are subsequently added. After1.39 ml of triethylamine have been added dropwise, the reaction mixtureis stirred at room temperature for two days. Conventional work-up of themixture gives compound 16 (m.p. 193-195° C.).

The following preferred NHE-3 inhibitors were obtained as acid-additionsalts or free bases analogously to the processes indicated above usingthe corresponding precursors:

pTsOH below denotes p-toluenesulfonic acid.

Examples 9-44

R¹ R² R³ R⁴ nHA  (9) H Cl H H pTsOH (10) H Cl CH₃ H HCl m.p. 289-290° C.(11) H Cl C₂H₅ H HCl (12) H Cl OCH₃ H HCl (13) H Cl NO₂ H HCl (14) H ClNH₂ H pTsOH (15) H Cl N(CH₃)₂ H pTsOH (16) H Cl H NH₂ HCl (17) H Cl CH₃NH₂ pTsOH (18) H Cl C₂H₅ NH₂ HCl (19) H Cl OCH₃ NH₂ HCl (20) H Cl NO₂NH₂ HCl (21) H Cl NH₂ NH₂ HCl (22) H Cl N(CH₃)₂ NH₂ HCl (23) H Cl HNHCH₃ HCl (24) H Cl CH₃ NHCH₃ HCl (25) H Cl C₂H₅ NHCH₃ HCl (26) H ClOCH₃ NHCH₃ HCl (27) H Cl NO₂ NHCH₃ HCl (28) H Cl NH₂ NHCH₃ HCl (29) H ClN(CH₃)₂ NHCH₃ HCl (30) H Cl H N(CH₃)₂ HCl (31) H Cl CH₃ N(CH₃)₂ HCl (32)H Cl C₂H₅ N(CH₃)₂ HCl (33) H Cl OCH₃ N(CH₃)₂ HCl (34) H Cl NO₂ N(CH₃)₂HCl (35) H Cl NH₂ N(CH₃)₂ HCl (36) H Cl N(CH₃)₂ N(CH₃)₂ HCl (37) H Cl HOH HCl (38) H Cl CH₃ OH HCl (39) H Cl C₂H₅ OH HCl (40) H Cl OCH₃ OH HCl(41) H Cl NO₂ OH HCl (42) H Cl NH₂ OH HCl (43) H Cl N(CH₃)₂ OH HCl (44)H Cl SO₂CH₃ CH₃ HCl

Examples 45-80

R¹ R² R³ R⁴ nHA (45) H Cl H H pTsOH (46) H Cl CH₃ H HCl (47) H Cl C₂H₅ HHCl (48) H Cl OCH₃ H HCl (49) H Cl NO₂ H HCl (50) H Cl NH₂ H pTsCO (51)H Cl N(CH₃)₂ H pTsOH (52) H Cl H NH₂ HCl (53) H Cl CH₃ NH₂ pTsOH (54) HCl C₂H₅ NH₂ HCl (55) H Cl OCH₃ NH₂ HCl (56) H Cl NO₂ NH₂ HCl (57) H ClNH₂ NH₂ HCl (58) H Cl N(CH₃)₂ NH₂ HCl (59) H Cl H NHCH₃ HCl (60) H ClCH₃ NHCH₃ HCl (61) H Cl C₂H₅ NHCH₃ HCl (62) H Cl OCH₃ NHCH₃ HCl (63) HCl NO₂ NHCH₃ HCl (64) H Cl NH₂ NHCH₃ HCl (65) H Cl N(CH₃)₂ NHCH₃ HCl(66) H Cl H N(CH₃)₂ HCl (67) H Cl CH₃ N(CH₃)₂ HCl (68) H Cl C₂H₅ N(CH₃)₂HCl (69) H Cl OCH₃ N(CH₃)₂ HCl (70) H Cl NO₂ N(CH₃)₂ HCl (71) H Cl NH₂N(CH₃)₂ HCl (72) H Cl N(CH₃)₂ N(CH₃)₂ HCl (73) H Cl H OH HCl (74) H ClCH₃ OH HCl (75) H Cl C₂H₅ OH HCl (76) H Cl OCH₃ OH HCl (77) H Cl NO₂ OHHCl (78) H Cl NH₂ OH HCl (79) H Cl N(CH₃)₂ OH HCl (80) H Cl SO₂CH₃ CH₃HCl

Examples 81-116

R¹ R² R³ R⁴ nHA  (81) H Cl H H pTsOH  (82) H Cl CH₃ H HCl  (83) H ClC₂H₅ H HCl  (84) H Cl OCH₃ H HCl  (85) H Cl NO₂ H HCl  (86) H Cl NH₂ HpTsOH  (87) H Cl N(CH₃)₂ H pTsOH  (88) H Cl H NH₂ HCl  (89) H Cl CH₃ NH₂pTsOH  (90) H Cl C₂H₅ NH₂ HCl  (91) H Cl OCH₃ NH₂ HCl  (92) H Cl NO₂ NH₂HCl  (93) H Cl NH₂ NH₂ HCl  (94) H Cl N(CH₃)₂ NH₂ HCl  (95) H Cl H NHCH₃HCl  (96) H Cl CH₃ NHCH₃ HCl  (97) H Cl C₂H₅ NHCH₃ HCl  (98) H Cl OCH₃NHCH₃ HCl  (99) H Cl NO₂ NHCH₃ HCl (100) H Cl NH₂ NHCH₃ HCl (101) H ClN(CH₃)₂ NHCH₃ HCl (102) H Cl H N(CH₃)₂ HCl (103) H Cl CH₃ N(CH₃)₂ HCl(104) H Cl C₂H₅ N(CH₃)₂ HCl (105) H Cl OCH₃ N(CH₃)₂ HCl (106) H Cl NO₂N(CH₃)₂ HCl (107) H Cl NH₂ N(CH₃)₂ HCl (108) H Cl N(CH₃)₂ N(CH₃)₂ HCl(109) H Cl H OH HCl (110) H Cl CH₃ OH HCl (111) H Cl C₂H₅ OH HCl (112) HCl OCH₃ OH HCl (113) H Cl NO₂ OH HCl (114) H Cl NH₂ OH HCl (115) H ClN(CH₃)₂ OH HCl (116) H Cl SO₂CH₃ CH₃ HCl

Examples 117-152

R¹ R² R³ R⁴ nHA (117) H Cl H H pTsOH (118) H Cl CH₃ H HCl (119) H ClC₂H₅ H HCl (120) H Cl OCH₃ H HCl (121) H Cl NO₂ H HCl (122) H Cl NH₂ HpTsOH (123) H Cl N(CH₃)₂ H pTsOH (124) H Cl H NH₂ HCl (125) H Cl CH₃ NH₂pTsOH (126) H Cl C₂H₅ NH₂ HCl (127) H Cl OCH₃ NH₂ HCl (128) H Cl NO₂ NH₂HCl (129) H Cl NH₂ NH₂ HCl (130) H Cl N(CH₃)₂ NH₂ HCl (131) H Cl H NHCH₃HCl (132) H Cl CH₃ NHCH₃ HCl (133) H Cl C₂H₅ NHCH₃ HCl (134) H Cl OCH₃NHCH₃ HCl (135) H Cl NO₂ NHCH₃ HCl (136) H Cl NH₂ NHCH₃ HCl (137) H ClN(CH₃)₂ NHCH₃ HCl (138) H Cl H N(CH₃)₂ HCl (139) H Cl CH₃ N(CH₃)₂ HCl(140) H Cl C₂H₅ N(CH₃)₂ HCl (141) H Cl OCH₃ N(CH₃)₂ HCl (142) H Cl NO₂N(CH₃)₂ HCl (143) H Cl NH₂ N(CH₃)₂ HCl (144) H Cl N(CH₃)₂ N(CH₃)₂ HCl(145) H Cl H OH HCl (146) H Cl CH₃ OH HCl (147) H Cl C₂H₅ OH HCl (148) HCl OCH₃ OH HCl (149) H Cl NO₂ OH HCl (150) H Cl NH₂ OH HCl (151) H ClN(CH₃)₂ OH HCl (152) H Cl SO₂CH₃ CH₃ HCl

Examples 153-188

R¹ R² R³ R⁴ nHA (153) H Cl H H pTsOH (154) H Cl CH₃ H pTsOH (155) H ClC₂H₅ H HCl (156) H Cl OCH₃ H HCl (157) H Cl NO₂ H HCl (158) H Cl NH₂ HpTsOH (159) H Cl N(CH₃)₂ H pTsOH (160) H Cl H NH₂ HCl (161) H Cl CH₃ NH₂pTsOH (162) H Cl C₂H₅ NH₂ HCl (163) H Cl OCH₃ NH₂ HCl (164) H Cl NO₂ NH₂HCl (165) H Cl NH₂ NH₂ HCl (166) H Cl N(CH₃)₂ NH₂ HCl (167) H Cl H NHCH₃HCl (168) H Cl CH₃ NHCH₃ HCl (169) H Cl C₂H₅ NHCH₃ HCl (170) H Cl OCH₃NHCH₃ HCl (171) H Cl NO₂ NHCH₃ HCl (172) H Cl NH₂ NHCH₃ HCl (173) H ClN(CH₃)₂ NHCH₃ HCl (174) H Cl H N(CH₃)₂ HCl (175) H Cl CH₃ N(CH₃)₂ HCl(176) H Cl C₂H₅ N(CH₃)₂ HCl (177) H Cl OCH₃ N(CH₃)₂ HCl (178) H Cl NO₂N(CH₃)₂ HCl (179) H Cl NH₂ N(CH₃)₂ HCl (180) H Cl N(CH₃)₂ N(CH₃)₂ HCl(181) H Cl H OH HCl (182) H Cl CH₃ OH HCl (183) H Cl C₂H₅ OH HCl (184) HCl OCH₃ OH HCl (185) H Cl NO₂ OH HCl (186) H Cl NH₂ OH HCl (187) H ClN(CH₃)₂ OH HCl (188) H Cl SO₂CH₃ CH₃ HCl

Examples 189-224

R¹ R² R³ R⁴ nHA (189) H Cl H H pTsOH (190) H Cl CH₃ H HCl (191) H ClC₂H₅ H HCl (192) H Cl OCH₃ H HCl (193) H Cl NO₂ H HCl (194) H Cl NH₂ HpTsOH (195) H Cl N(CH₃)₂ H pTsOH (196) H Cl H NH₂ HCl (197) H Cl CH₃ NH₂pTsOH (198) H Cl C₂H₅ NH₂ HCl (199) H Cl OCH₃ NH₂ HCl (200) H Cl NO₂ NH₂HCl (201) H Cl NH₂ NH₂ HCl (202) H Cl N(CH₃)₂ NH₂ HCl (203) H Cl H NHCH₃HCl (204) H Cl CH₃ NHCH₃ HCl (205) H Cl C₂H₅ NHCH₃ HCl (206) H Cl OCH₃NHCH₃ HCl (207) H Cl NO₂ NHCH₃ HCl (208) H Cl NH₂ NHCH₃ HCl (209) H ClN(CH₃)₂ NHCH₃ HCl (210) H Cl H N(CH₃)₂ HCl (211) H Cl CH₃ N(CH₃)₂ HCl(212) H Cl C₂H₅ N(CH₃)₂ HCl (213) H Cl OCH₃ N(CH₃)₂ HCl (214) H Cl NO₂N(CH₃)₂ HCl (215) H Cl NH₂ N(CH₃)₂ HCl (216) H Cl N(CH₃)₂ N(CH₃)₂ HCl(217) H Cl H OH HCl (218) H Cl CH₃ OH HCl (219) H Cl C₂H₅ OH HCl (220) HCl OCH₃ OH HCl (221) H Cl NO₂ OH HCl (222) H Cl NH₂ OH HCl (223) H ClN(CH₃)₂ OH HCl (224) H Cl SO₂CH₃ CH₃ HCl

Examples 225-260

R¹ R² R³ R⁴ nHA (225) H Cl H H 3 HCl m.p. 241° C. (226) H Cl CH₃ H HCl(227) H Cl C₂H₅ H HCl (228) H Cl OCH₃ H HCl (229) H Cl NO₂ H HCl (230) HCl NH₂ H pTsOH (231) H Cl N(CH₃)₂ H pTsOH (232) H Cl H NH₂ HCl (233) HCl CH₃ NH₂ pTsOH (234) H Cl C₂H₅ NH₂ HCl (235) H Cl OCH₃ NH₂ HCl (236) HCl NO₂ NH₂ HCl (237) H Cl NH₂ NH₂ HCl (238) H Cl N(CH₃)₂ NH₂ HCl (239) HCl H NHCH₃ HCl (240) H Cl CH₃ NHCH₃ HCl (241) H Cl C₂H₅ NHCH₃ HCl (242)H Cl OCH₃ NHCH₃ HCl (243) H Cl NO₂ NHCH₃ HCl (244) H Cl NH₂ NHCH₃ HCl(245) H Cl N(CH₃)₂ NHCH₃ HCl (246) H Cl H N(CH₃)₂ HCl (247) H Cl CH₃N(CH₃)₂ HCl (248) H Cl C₂H₅ N(CH₃)₂ HCl (249) H Cl OCH₃ N(CH₃)₂ HCl(250) H Cl NO₂ N(CH₃)₂ HCl (251) H Cl NH₂ N(CH₃)₂ HCl (252) H Cl N(CH₃)₂N(CH₃)₂ HCl (253) H Cl H OH HCl (254) H Cl CH₃ OH HCl (255) H Cl C₂H₅ OHHCl (256) H Cl OCH₃ OH HCl (257) H Cl NO₂ OH HCl (258) H Cl NH₂ OH HCl(259) H Cl N(CH₃)₂ OH HCl (260) H Cl SO₂CH₃ CH₃ HCl

Examples 261-296

R¹ R² R³ R⁴ nHA (261) H Cl H H 2 pTsOH (262) H Cl CH₃ H HCl (263) H ClC₂H₅ H HCl (264) H Cl OCH₃ H HCl (265) H Cl NO₂ H HCl (266) H Cl NH₂ HpTsOH (267) H Cl N(CH₃)₂ H pTsOH (268) H Cl H NH₂ HCl (269) H Cl CH₃ NH₂pTsOH (270) H Cl C₂H₅ NH₂ HCl (271) H Cl OCH₃ NH₂ HCl (272) H Cl NO₂ NH₂HCl (273) H Cl NH₂ NH₂ HCl (274) H Cl N(CH₃)₂ NH₂ HCl (275) H Cl H NHCH₃HCl (276) H Cl CH₃ NHCH₃ HCl (277) H Cl C₂H₅ NHCH₃ HCl (278) H Cl OCH₃NHCH₃ HCl (279) H Cl NO₂ NHCH₃ HCl (280) H Cl NH₂ NHCH₃ HCl (281) H ClN(CH₃)₂ NHCH₃ HCl (282) H Cl H N(CH₃)₂ HCl (283) H Cl CH₃ N(CH₃)₂ HCl(284) H Cl C₂H₅ N(CH₃)₂ HCl (285) H Cl OCH₃ N(CH₃)₂ HCl (286) H Cl NO₂N(CH₃)₂ HCl (287) H Cl NH₂ N(CH₃)₂ HCl (288) H Cl N(CH₃)₂ N(CH₃)₂ HCl(289) H Cl H OH HCl (290) H Cl CH₃ OH HCl (291) H Cl C₂H₅ OH HCl (292) HCl OCH₃ OH HCl (293) H Cl NO₂ OH HCl (294) H Cl NH₂ OH HCl (295) H ClN(CH₃)₂ OH HCl (296) H Cl SO₂CH₃ CH₃ HCl

Examples 297-332

R¹ R² R³ R⁴ nHA (297) H Cl H H 2 HCl m.p. 137° C. (298) H Cl CH₃ H HCl(299) H Cl C₂H₅ H HCl (300) H Cl OCH₃ H HCl (301) H Cl NO₂ H HCl (302) HCl NH₂ H pTsOH (303) H Cl N(CH₃)₂ H pTsOH (304) H Cl H NH₂ HCl (305) HCl CH₃ NH₂ pTsOH (306) H Cl C₂H₅ NH₂ HCl (307) H Cl OCH₃ NH₂ HCl (308) HCl NO₂ NH₂ HCl (309) H Cl NH₂ NH₂ HCl (310) H Cl N(CH₃)₂ NH₂ HCl (311) HCl H NHCH₃ HCl (312) H Cl CH₃ NHCH₃ HCl (313) H Cl C₂H₅ NHCH₃ HCl (314)H Cl OCH₃ NHCH₃ HCl (315) H Cl NO₂ NHCH₃ HCl (316) H Cl NH₂ NHCH₃ HCl(317) H Cl N(CH₃)₂ NHCH₃ HCl (318) H Cl H N(CH₃)₂ HCl (319) H Cl CH₃N(CH₃)₂ HCl (320) H Cl C₂H₅ N(CH₃)₂ HCl (321) H Cl OCH₃ N(CH₃)₂ HCl(322) H Cl NO₂ N(CH₃)₂ HCl (323) H Cl NH₂ N(CH₃)₂ HCl (324) H Cl N(CH₃)₂N(CH₃)₂ HCl (325) H Cl H OH HCl (326) H Cl CH₃ OH HCl (327) H Cl C₂H₅ OHHCl (328) H Cl OCH₃ OH HCl (329) H Cl NO₂ OH HCl (330) H Cl NH₂ OH HCl(331) H Cl N(CH₃)₂ OH HCl (332) H Cl SO₂CH₃ CH₃ HCl

Examples 333-368

R¹ R² R³ R⁴ nHA (333) H Cl H H 3 HCl m.p. >160° C. (334) H Cl CH₃ H HCl(335) H Cl C₂H₅ H HCl (336) H Cl OCH₃ H HCl (337) H Cl NO₂ H HCl (338) HCl NH₂ H pTsOH (339) H Cl N(CH₃)₂ H pTsOH (340) H Cl H NH₂ HCl (341) HCl CH₃ NH₂ pTsOH (342) H Cl C₂H₅ NH₂ HCl (343) H Cl OCH₃ NH₂ HCl (344) HCl NO₂ NH₂ HCl (345) H Cl NH₂ NH₂ HCl (346) H Cl N(CH₃)₂ NH₂ HCl (347) HCl H NHCH₃ HCl (348) H Cl CH₃ NHCH₃ HCl (349) H Cl C₂H₅ NHCH₃ HCl (350)H Cl OCH₃ NHCH₃ HCl (351) H Cl NO₂ NHCH₃ HCl (352) H Cl NH₂ NHCH₃ HCl(353) H Cl N(CH₃)₂ NHCH₃ HCl (354) H Cl H N(CH₃)₂ HCl (355) H Cl CH₃N(CH₃)₂ HCl (356) H Cl C₂H₅ N(CH₃)₂ HCl (357) H Cl OCH₃ N(CH₃)₂ HCl(358) H Cl NO₂ N(CH₃)₂ HCl (359) H Cl NH₂ N(CH₃)₂ HCl (360) H Cl N(CH₃)₂N(CH₃)₂ HCl (361) H Cl H OH HCl (362) H Cl CH₃ OH HCl (363) H Cl C₂H₅ OHHCl (364) H Cl OCH₃ OH HCl (365) H Cl NO₂ OH HCl (366) H Cl NH₂ OH HCl(367) H Cl N(CH₃)₂ OH HCl (368) H Cl SO₂CH₃ CH₃ HCl

Examples 369-404

R¹ R² R³ R⁴ nHA (369) H Cl H H pTsOH (370) H Cl CH₃ H HCl (371) H ClC₂H₅ H HCl (372) H Cl OCH₃ H HCl (373) H Cl NO₂ H HCl (374) H Cl NH₂ HpTsOH (375) H Cl N(CH₃)₂ H pTsOH (376) H Cl H NH₂ HCl (377) H Cl CH₃ NH₂pTsOH (378) H Cl C₂H₅ NH₂ HCl (379) H Cl OCH₃ NH₂ HCl (380) H Cl NO₂ NH₂HCl (381) H Cl NH₂ NH₂ HCl (382) H Cl N(CH₃)₂ NH₂ HCl (383) H Cl H NHCH₃HCl (384) H Cl CH₃ NHCH₃ HCl (385) H Cl C₂H₅ NHCH₃ HCl (386) H Cl OCH₃NHCH₃ HCl (387) H Cl NO₂ NHCH₃ HCl (388) H Cl NH₂ NHCH₃ HCl (389) H ClN(CH₃)₂ NHCH₃ HCl (390) H Cl H N(CH₃)₂ HCl (391) H Cl CH₃ N(CH₃)₂ HCl(392) H Cl C₂H₅ N(CH₃)₂ HCl (393) H Cl OCH₃ N(CH₃)₂ HCl (394) H Cl NO₂N(CH₃)₂ HCl (395) H Cl NH₂ N(CH₃)₂ HCl (396) H Cl N(CH₃)₂ N(CH₃)₂ HCl(397) H Cl H OH HCl (398) H Cl CH₃ OH HCl (399) H Cl C₂H₅ OH HCl (400) HCl OCH₃ OH HCl (401) H Cl NO₂ OH HCl (402) H Cl NH₂ OH HCl (403) H ClN(CH₃)₂ OH HCl (404) H Cl SO₂CH₃ CH₃ HCl

Examples 405-440

R¹ R² R³ R⁴ nHA (405) H Cl H H 3 HCl m.p. 240° C. (406) H Cl CH₃ H HCl(407) H Cl C₂H₅ H HCl (408) H Cl OCH₃ H HCl (409) H Cl NO₂ H HCl (410) HCl NH₂ H pTsOH (411) H Cl N(CH₃)₂ H pTsOH (412) H Cl H NH₂ HCl (413) HCl CH₃ NH₂ pTsOH (414) H Cl C₂H₅ NH₂ HCl (415) H Cl OCH₃ NH₂ HCl (416) HCl NO₂ NH₂ HCl (417) H Cl NH₂ NH₂ HCl (418) H Cl N(CH₃)₂ NH₂ HCl (419) HCl H NHCH₃ HCl (420) H Cl CH₃ NHCH₃ HCl (421) H Cl C₂H₅ NHCH₃ HCl (422)H Cl OCH₃ NHCH₃ HCl (423) H Cl NO₂ NHCH₃ HCl (424) H Cl NH₂ NHCH₃ HCl(425) H Cl N(CH₃)₂ NHCH₃ HCl (426) H Cl H N(CH₃)₂ HCl (427) H Cl CH₃N(CH₃)₂ HCl (428) H Cl C₂H₅ N(CH₃)₂ HCl (429) H Cl OCH₃ N(CH₃)₂ HCl(430) H Cl NO₂ N(CH₃)₂ HCl (431) H Cl NH₂ N(CH₃)₂ HCl (432) H Cl N(CH₃)₂N(CH₃)₂ HCl (433) H Cl H OH HCl (434) H Cl CH₃ OH HCl (435) H Cl C₂H₅ OHHCl (436) H Cl OCH₃ OH HCl (437) H Cl NO₂ OH HCl (438) H Cl NH₂ OH HCl(439) H Cl N(CH₃)₂ OH HCl (440) H Cl SO₂CH₃ CH₃ HCl

Examples 441-476

R¹ R² R³ R⁴ nHA (441) H Cl H H pTsOH (442) H Cl CH₃ H HCl (443) H ClC₂H₅ H HCl (444) H Cl OCH₃ H HCl (445) H Cl NO₂ H HCl (446) H Cl NH₂ HpTsOH (447) H Cl N(CH₃)₂ H pTsOH (448) H Cl H NH₂ HCl (449) H Cl CH₃ NH₂pTsOH (450) H Cl C₂H₅ NH₂ HCl (451) H Cl OCH₃ NH₂ HCl (452) H Cl NO₂ NH₂HCl (453) H Cl NH₂ NH₂ HCl (454) H Cl N(CH₃)₂ NH₂ HCl (455) H Cl H NHCH₃HCl (456) H Cl CH₃ NHCH₃ HCl (457) H Cl C₂H₅ NHCH₃ HCl (458) H Cl OCH₃NHCH₃ HCl (459) H Cl NO₂ NHCH₃ HCl (460) H Cl NH₂ NHCH₃ HCl (461) H ClN(CH₃)₂ NHCH₃ HCl (462) H Cl H N(CH₃)₂ HCl (463) H Cl CH₃ N(CH₃)₂ HCl(464) H Cl C₂H₅ N(CH₃)₂ HCl (465) H Cl OCH₃ N(CH₃)₂ HCl (466) H Cl NO₂N(CH₃)₂ HCl (467) H Cl NH₂ N(CH₃)₂ HCl (468) H Cl N(CH₃)₂ N(CH₃)₂ HCl(469) H Cl H OH HCl (470) H Cl CH₃ OH HCl (471) H Cl C₂H₅ OH HCl (472) HCl OCH₃ OH HCl (473) H Cl NO₂ OH HCl (474) H Cl NH₂ OH HCl (475) H ClN(CH₃)₂ OH HCl (476) H Cl SO₂CH₃ CH₃ HCl

Examples 477-512

R¹ R² R³ R⁴ nHA (477) H Cl H H HCl m.p. 170° C. (478) H Cl CH₃ H HCl(479) H Cl C₂H₅ H HCl (480) H Cl OCH₃ H HCl (481) H Cl NO₂ H HCl (482) HCl NH₂ H pTsOH (483) H Cl N(CH₃)₂ H pTsOH (484) H Cl H NH₂ HCl (485) HCl CH₃ NH₂ pTsOH (486) H Cl C₂H₅ NH₂ HCl (487) H Cl OCH₃ NH₂ HCl (488) HCl NO₂ NH₂ HCl (489) H Cl NH₂ NH₂ HCl (490) H Cl N(CH₃)₂ NH₂ HCl (491) HCl H NHCH₃ HCl (492) H Cl CH₃ NHCH₃ HCl (493) H Cl C₂H₅ NHCH₃ HCl (494)H Cl OCH₃ NHCH₃ HCl (495) H Cl NO₂ NHCH₃ HCl (496) H Cl NH₂ NHCH₃ HCl(497) H Cl N(CH₃)₂ NHCH₃ HCl (498) H Cl H N(CH₃)₂ HCl (499) H Cl CH₃N(CH₃)₂ HCl (500) H Cl C₂H₅ N(CH₃)₂ HCl (501) H Cl OCH₃ N(CH₃)₂ HCl(502) H Cl NO₂ N(CH₃)₂ HCl (503) H Cl NH₂ N(CH₃)₂ HCl (504) H Cl N(CH₃)₂N(CH₃)₂ HCl (505) H Cl H OH HCl (506) H Cl CH₃ OH HCl (507) H Cl C₂H₅ OHHCl (508) H Cl OCH₃ OH HCl (509) H Cl NO₂ OH HCl (510) H Cl NH₂ OH HCl(511) H Cl N(CH₃)₂ OH HCl (512) H Cl SO₂CH₃ CH₃ HCl

Examples 513-548

R¹ R² R³ R⁴ nHA (513) H Cl H H 2 HCl m.p. 207° C. (514) H Cl CH₃ H HCl(515) H Cl C₂H₅ H HCl (516) H Cl OCH₃ H HCl (517) H Cl NO₂ H HCl (518) HCl NH₂ H pTsOH (519) H Cl N(CH₃)₂ H pTsOH (520) H Cl H NH₂ HCl (521) HCl CH₃ NH₂ pTsOH (522) H Cl C₂H₅ NH₂ HCl (523) H Cl OCH₃ NH₂ HCl (524) HCl NO₂ NH₂ HCl (525) H Cl NH₂ NH₂ HCl (526) H Cl N(CH₃)₂ NH₂ HCl (527) HCl H NHCH₃ HCl (528) H Cl CH₃ NHCH₃ HCl (529) H Cl C₂H₅ NHCH₃ HCl (530)H Cl OCH₃ NHCH₃ HCl (531) H Cl NO₂ NHCH₃ HCl (532) H Cl NH₂ NHCH₃ HCl(533) H Cl N(CH₃)₂ NHCH₃ HCl (534) H Cl H N(CH₃)₂ HCl (535) H Cl CH₃N(CH₃)₂ HCl (536) H Cl C₂H₅ N(CH₃)₂ HCl (537) H Cl OCH₃ N(CH₃)₂ HCl(538) H Cl NO₂ N(CH₃)₂ HCl (539) H Cl NH₂ N(CH₃)₂ HCl (540) H Cl N(CH₃)₂N(CH₃)₂ HCl (541) H Cl H OH HCl (542) H Cl CH₃ OH HCl (543) H Cl C₂H₅ OHHCl (544) H Cl OCH₃ OH HCl (545) H Cl NO₂ OH HCl (546) H Cl NH₂ OH HCl(547) H Cl N(CH₃)₂ OH HCl (548) H Cl SO₂CH₃ CH₃ HCl

Examples 549-584

R¹ R² R³ R⁴ nHA (549) H Cl H H pTsQH (550) H Cl CH₃ H HCl (551) H ClC₂H₅ H HCl (552) H Cl OCH₃ H HCl (553) H Cl NO₂ H HCl (554) H Cl NH₂ HpTsOH (555) H Cl N(CH₃)₂ H pTsOH (556) H Cl H NH₂ HCl (557) H Cl CH₃ NH₂pTsOH (558) H Cl C₂H₅ NH₂ HCl (559) H Cl OCH₃ NH₂ HCl (560) H Cl NO₂ NH₂HCl (561) H Cl NH₂ NH₂ HCl (562) H Cl N(CH₃)₂ NH₂ HCl (563) H Cl H NHCH₃HCl (564) H Cl CH₃ NHCH₃ HCl (565) H Cl C₂H₅ NHCH₃ HCl (566) H Cl OCH₃NHCH₃ HCl (567) H Cl NO₂ NHCH₃ HCl (568) H Cl NH₂ NHCH₃ HCl (569) H ClN(CH₃)₂ NHCH₃ HCl (570) H Cl H N(CH₃)₂ HCl (571) H Cl CH₃ N(CH₃)₂ HCl(572) H Cl C₂H₅ N(CH₃)₂ HCl (573) H Cl OCH₃ N(CH₃)₂ HCl (574) H Cl NO₂N(CH₃)₂ HCl (575) H Cl NH₂ N(CH₃)₂ HCl (576) H Cl N(CH₃)₂ N(CH₃)₂ HCl(577) H Cl H OH HCl (578) H Cl CH₃ OH HCl (579) H Cl C₂2H₅ OH HCl (580)H Cl OCH₃ OH HCl (581) H Cl NO₂ OH HCl (582) H Cl NH₂ OH HCl (583) H ClN(CH₃)₂ OH HCl (584) H Cl SO₂CH₃ OH₃ HClPharmacological Tests

The method used for the characterisation of the compounds of the formulaI as NHE-3 inhibitors is described below.

The compounds of the formula I are characterised with respect to theirselectivity for the NHE-1 to NHE-3 isoforms. The three isoforms areexpressed in stable form in mouse fibroblast cell lines. The inhibitoryaction of the compounds is assessed by determination of theEIPA-sensitive uptake of ²²Na⁺ into the cells after intracellularacidosis.

Material and Methods

LAP1 Cell Lines Which Express the Different NHE Isoforms

The LAP1 cell lines which express the NHE-1, -2 and -3 isoforms (a mousefibroblast cell line) is obtained from Prof. J. Pouysségur (Nice,France). The transfection is carried out by the method of Franchi et al.(1986). The cells are cultivated in Dulbeccos modified eagle medium(DMEM) with 10% of deactivated foetal calf serum (FCS). For selection ofthe NHE-expressing cells, the so-called “acid killing method” of Sardetet al. (1989) is used. The cells are firstly incubated for 30 minutes inan NH₄Cl-containing bicarbonate- and sodium-free buffer. Theextracellular NH₄Cl is then removed by washing with a bicarbonate-,NH₄Cl- and sodium-free buffer. The cells are subsequently incubated in abicarbonate-free NaCl-containing buffer. Only those cells whichfunctionally express NHE are able to survive the intracellularacidification to which they are subjected.

Characterisation of NHE Inhibitors with Respect to Their IsoformSelectivity

With the above-mentioned mouse fibroblast cell lines which express theNHE-1, NHE-2 and NHE-3 isoforms, compounds are tested for selectivitywith respect to the isoforms by the procedure described by Counillon etal. (1993) and Scholz et al. (1995). The cells are acidifiedintracellularly by the NH₄Cl prepulse method and subsequently byincubation in a bicarbonate-free ²²Na⁺-containing buffer. Owing to theintracellular acidification, NHE is activated, and sodium is taken upinto the cells. The effect of the test compound is expressed asinhibition of EIPA (ethylisopropylamiloride)-sensitive ²²Na⁺ take-up.

The cells which expressed NHE-1, NHE-2 and NHE-3 are sown out in adensity of 5-7.5×10⁴ cells/well in 24-well microtitre plates andcultured to confluence for from 24 to 48 hours. The medium is removed bysuction, and the cells are incubated for 60 minutes at 37° C. in NH₄Clbuffer (50 mM NH₄Cl, 70 mM choline chloride, 15 mM MOPS, pH 7.0). Thebuffer is subsequently removed, and the cells are rapidly covered twicewith the choline chloride wash buffer (120 mM choline chloride, 15 mMPIPES/tris, 0.1 mM ouabain, 1 mM MgCl₂, 2 mM CaCl₂, pH 7.4) and filteredoff with suction. The cells are subsequently covered with the cholinechloride charging buffer (120 mM choline chloride, 15 mM PIPES/tris, 0.1mM PIPES/tris, 0.1 mM ouabain, 1 mM MgCl₂, 2 mM CaCl₂, pH 7.4, ²²Na⁺(0.925 kBg/100 ml of charging buffer)) and then incubated in this bufferfor 6 minutes. After expiry of the incubation time, the incubationbuffer is removed by suction. In order to remove extracellularradioactivity, the cells are washed rapidly four times with ice-coldphosphate-buffered saline solution (PBS). The cells are then solubilisedby addition of 0.3 ml of 0.1 N NaOH per well. The cellfragment-containing solutions are transferred into scintillation tubes.Each well is then washed twice with 0.3 ml of 0.1 N NaOH, and thewashing solutions are likewise introduced into the correspondingscintillation tubes. Scintillation cocktail is added to the tubescontaining the cell lysate, and the radioactivity taken up into thecells is determined by determination of the p radiation.

Literature:

-   Counillon et al. (1993) Mol. Pharmacol. 44: 1041-1045-   Franchi et al. (1986) Proc. Natl. Acad. Sci. USA 83: 9388-9392-   Sardet et al. (1989) Cell 56: 271-280-   Scholz et al. (1995) Cardiovasc. Res. 29: 260-268

The examples below relate to pharmaceutical preparations:

Example A Injection Vials

A solution of 100 g of an NHE-3 inhibitor of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions.

Each injection vial contains 5 mg of active ingredient.

Example B Suppositories

A mixture of 20 g of an NHE-3 inhibitor of the formula I is melted with100 g of soya lecithin and 1400 g of cocoa butter, poured into mouldsand allowed to cool. Each suppository contains 20 mg of activeingredient.

Example C Solution

A solution is prepared from 1 g of an NHE-3 inhibitor of the formula I,9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

Example D Ointment

500 mg of an NHE-3 inhibitor of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

Example E Tablets

A mixture of 1 kg of an NHE-3 inhibitor of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed to give tablets in a conventional manner in such away that each tablet contains 10 mg of active ingredient.

Example F Coated Tablets

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

Example G Capsules

2 kg of an NHE-3 inhibitor of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

Example H Ampoules

A solution of 1 kg of an NHE-3 inhibitor of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. Compounds of the formula I

in which Ar is X-substituted phenyl or naphthyl, which is additionallysubstituted by R³ and R⁴, Y is

X is H, NR⁶R⁷ or a saturated 5-7-membered ring having two N atoms, R¹,R², R³ and R⁴ are each, independently of one another, H, A, OA, Hal,CF₃, OH, NO₂, NH₂, NHA, NA₂, NH—CO-A, NH—CO-Ph, SA, SO-A, SO₂-A, SO₂-Ph,CN, OCF₃, CO-A, CO₂H, CO₂A, CO—NH₂, CO—NHA, CO—NA₂, SO₂NH₂, SO₂NHA,SO₂NA₂, or phenyl which is unsubstituted or monosubstituted orpolysubstituted by A, OA, Hal or CF₃, A is alkyl having 1, 2, 3, 4, 5 or6 carbon atoms, Hal is F, Cl, Br or I, R⁵ is H, A, OH, NO₂, phenyl whichis unsubstituted or monosubstituted or polysubstituted by A, OA, Hal orCF₃, an amino-protecting group or

R⁶ and R⁷ are each, independently of one another, H, A, phenyl which isunsubstituted or monosubstituted or polysubstituted by A, OA, Hal orCF₃, benzyl, an amino-protecting group or —(CH₂)_(n)NR¹⁰R¹¹, R⁸ and R⁹are each, independently of one another, H or A, R¹⁰ and R¹¹ are each,independently of one another, H, A, phenyl which is unsubstituted ormonosubstituted or polysubstituted by A, OA, Hal or CF₃, benzyl or anamino-protecting group, z is 0 or 1, and n is 2, 3 or 4, and salts,solvates and stereoisomers thereof, including mixtures thereof in allratios, and pharmaceutically usable derivatives thereof, in particularphysiologically tolerated salts and solvates thereof, with the provisothat compounds of the formula I in which X is H and simultaneously z is0 are excluded.
 2. Compounds of the formula I according to claim 1,characterised in that Ar has one of the following meanings:

in which R³, R⁴ and X are as defined above.
 3. Compounds of the formulaI according to claim 1, characterised in that at least one of theradicals R¹, R², R³ and R⁴ has one of the following meanings: Hal, A,OH, NO₂, NH₂, NHA, NA₂, NH—CO-A, NH—CO-Ph, SA, SO-A, SO₂-A, SO₂-Ph, CN,OCF₃, CO-A, CO₂H, CO₂A, CO—NH₂, CO—NHA, CO—NA₂, SO₂NH₂, SO₂NHA, SO₂NA₂,or phenyl which is unsubstituted or monosubstituted or polysubstitutedby A, OA, Hal or CF₃.
 4. Compounds of the formula I according to claim1, characterised in that R⁵ is H, A, OH, NO₂ or an amino-protectinggroup.
 5. Compounds of the formula I according to claim 1, characterisedin that R⁶ and R⁷ are simultaneously H, independently of one another H,A, benzyl or —(CH₂)_(n)NA₂.
 6. Compounds of the formula I according toclaim 1, characterised in that R⁸ and R⁹ are H or methyl.
 7. Compoundsof the formula I according to claim 1, characterised in that R¹⁰ and R¹¹are H, A, benzyl or phenyl.
 8. Compounds of the formula I according toclaim 1, characterised in that X is NR⁶R⁷, a 5- to 7-membered ringhaving 2 N atoms or the following radical:

in which R¹² is H, A, Ph, benzyl or an amino-protecting group. 9.Compounds of the formulae IA, IB and IC:

in which R¹, R², Het and Y are as defined in claim
 1. 10. Compounds ofthe formulae IA, IB and IC according to claim 9, in which R² is Cl. 11.Compounds of the formulae I1 to I10 and salts and solvates thereof:


12. Compounds of the formula I according to one or more of the precedingclaims and their salts and/or solvates as NHE-3 inhibitors. 13.Compounds of the formula I according to claim 1 and theirphysiologically acceptable salts and/or solvates for use in combatingillnesses.
 14. Use of compounds of the formula I according to claim 1and/or their physiologically acceptable salts or solvates for thepreparation of a medicament.
 15. Use of compounds of the formula Iaccording to claim 1 and/or their physiologically acceptable saltsand/or solvates for the preparation of a medicament for the treatmentand prophylaxis of hypertonia, thrombosis, ischaemic states of theheart, of the peripheral and central nervous system and of strokes,ischaemic states of peripheral organs and limbs, and for the treatmentof shock states.
 16. Use of compounds of the formula I according toclaim 1 and/or their physiologically acceptable salts and/or solvatesfor the preparation of a medicament for use in surgical operations andorgan transplants and for the preservation and storage of transplantsfor surgical measures.
 17. Use of compounds of the formula I accordingto claim 1 and/or their physiologically acceptable salts and/or solvatesfor the preparation of a medicament for the treatment and prophylaxis ofillnesses in which cell proliferation represents a primary or secondarycause, for the treatment or prophylaxis of disorders of fat metabolismor disturbed breathing drive.
 18. Use of compounds of the formula Iaccording to claim 1 and/or and their physiologically acceptable saltsand/or solvates for the preparation of a medicament for the treatmentand prophylaxis of renal ischaemia, ischaemic intestinal illnesses orfor the prophylaxis of acute or chronic renal illnesses.
 19. Use ofcompounds of the formula I according to claim 1 and/or theirphysiologically acceptable salts and/or solvates for the preparation ofa medicament for the treatment and prophylaxis of bacterial andparasitic illnesses.
 20. Pharmaceutical preparation, characterised by acontent of at least one NHE-3 inhibitor according to claim 1 and/or oneof its physiologically acceptable salts and/or solvates.
 21. Process forthe preparation of pharmaceutical preparations, characterised in that atleast one compound of the formula I according to claim 1 and/or one ofits physiologically acceptable salts and solvates is converted into asuitable dosage form together with at least one solid, liquid orsemi-liquid excipient or adjuvant.
 22. Use of compounds of the formula Iaccording to claim 1 and/or physiologically acceptable salts and/orsolvates thereof for the preparation of a medicament for the treatmentand prophylaxis of diseases which are caused by increased NHE activityand/or can be influenced by a reduction in NHE activity.
 23. Use ofcompounds of the formula I according to claim 1 and/or physiologicallyacceptable salts and/or solvates thereof for the preparation of amedicament for the treatment and prophylaxis of diseases or states whichare caused by increased uptake of sodium ions and water in cells byorgans which are undersupplied with oxygen.
 24. Medicament comprising atleast one compound of the formula I according to claim 1 and/orphysiologically acceptable salts and solvates thereof and at least onefurther medicament active ingredient.
 25. Set (kit) consisting ofseparate packs of (a) an effective amount of a compound of the formula Iaccording to claim 1 and/or physiologically acceptable salts andsolvates thereof and (b) an effective amount of a further medicamentactive ingredient.
 26. Compounds according to claim 1 as medicamentactive ingredients.
 27. Process for the preparation of the compounds ofthe formula I and salts and solvates thereof, characterised in thateither (a) compounds of the formula II

 in which R¹, R² and Ar are as defined in claim 1, are reacted with1-cyanoguanidine or a correspondingly N-alkylated or N-arylated1-cyanoguanidine of the formula NC—Y, in which Y is as defined in claim1 and z is 0, or (b) instead of a compound of the formula NC—Y, acompound of the formula IIIHN═CX—Y  III  in which X is —S-alkyl, —S-aryl, —O-alkyl or —O-aryl, andY is as defined in claim 1, where z is 0, is reacted with a compound ofthe formula II, or (c) compounds of the formula IV

 in which Ar, Hal, R¹ and R² are as defined above, are reacted with acompound of the formula HY, in which Y is as defined in claim 1, or (d)compounds of the formula VI

 are amidated using the corresponding nitrogen bases with palladiumcatalysis, and if desired, after steps (a), (b), (c) or (d), a basic oracidic compound of the formula I is converted into one of its salts orsolvates by treatment with an acid or base.